United States: Biotech Patent Dispute Between Academics That Is Far From Academic

On December 6, 2016, the parties to the complex and soon-to-be
departed world of patent interferences orally argued their
positions on motions in what has been described as the
"biotech trial of the century" and as "the biggest
biotech patent case in memory."[1] The parties' oral
arguments mirrored their motions, the most important of which rest
on whether the senior party's invention of the gene-editing
system CRISPR-Cas9 in bacteria (i.e. prokaryotic cells) rendered
obvious the use of the system in higher organisms (i.e. eukaryotic
cells), such as those of humans. The groundbreaking system
"has the potential to treat serious human genetic disorders
and create designer crops that resist drought and
pathogens"[2] and to reap billions for the victor. The
PTAB's decisions on motions might terminate the interference
without a priority phase. In any event, absent a settlement between
the academic contestants like that between the Pasteur Institute
and the National Cancer Institute over who first discovered the
cause of AIDS,[3] a higher authority than the PTAB will probably
provide the final decision in this monumental dispute.

The administrative patent judge managing the interference,
Deborah Katz, has a Ph.D. in molecular biology, which should serve
her well in this highly technical contest. The junior party, the
Broad Institute of Massachusetts Institute of Technology and the
president and fellows of Harvard College, has 12 patents and one
allowed application involved in the interference, all claiming
systems for gene editing in eukaryotes. The senior party, the
University of California and the University of Vienna, requested
the interference based on an application claiming only the system
for gene editing in prokaryotes, though disclosing use of the
system also in eukaryotes. The sole count in the interference as
declared reads as follows:

A method, in a eukaryotic cell, of cleaving or editing a target
DNA molecule or modulating transcription of at least one gene
encoded thereon, the method comprising:

a targeter-RNA or guide sequence that
hybridizes with the target sequence, and

an activator-RNA or tracr sequence
that hybridizes with the targeter-RNA to form a double-stranded RNA
duplex of a protein-binding segment,

and

a Cas9 protein,

wherein the DNA-targeting RNA forms a
complex with the Cas9 protein, thereby targeting the Cas9 protein
to the target DNA molecule, whereby said target DNA molecule is
cleaved or edited or transcription of at least one gene encoded by
the target DNA molecule is modulated.

Judge Katz designated all of the parties' claims as
corresponding to the count.

The key pending motions include:

Broad's motion for no
interference-in-fact (Broad substantive motion 2); and

Broad maintained in its motion for no interference-in-fact that
its claims to using the system in eukaryotic cells are separately
patentable over UC's claims, which are not limited to any
environment. Broad argued that in the 2012 time frame, its involved
claims were directed to unpredictable technology such that a person
of ordinary skill would not have had a reasonable expectation that
the claimed CRISPR-Cas9 system would have successfully cleaved or
edited the nuclear DNA of a eukaryotic cell. Broad relied heavily
on an admission by one of UC's inventors that development of a
CRISPR system for use in eukaryotic cells would be a "profound
discovery." Based on prior failures, Broad argued, "one
of skill in the art would not have had a reasonable expectation of
success in obtaining successful functioning of a CRISPR-Cas9 system
in eukaryotes."

UC countered that shortly after its inventors first published
their work on Type-II CRISPR-Cas9 system in Jinek et al., 337
SCIENCE 816-821 (2012) (Jinek 2012), in prokaryotic cells, an
independent group filed a patent application before Broad filed its
first provisional application on December 12, 2012, and several
independent groups, either before Broad filed its first provisional
application or at about the same time, drafted manuscripts, all
citing UC's publication as motivation and confirming the use of
UC's Type-II CRISPR-Cas system in eukaryotic cells. Both Broad
and the independent groups, UC argued, were able to quickly do so
because they used well-known conventional techniques that had been
routinely used to adapt other prokaryotic systems to eukaryotic
cells. For example, since prokaryotic cells do not have nuclei, one
of the independent groups tagged NLS (nuclear localization signal)
sequences to Cas9 and also codon-optimized it to successfully move
the Cas9 enzyme into the nuclei of eukaryotic cells. UC cited as
exemplary a provisional application filed by Dr. Kim et al. in
October 2012 that stated that UC's "seminal" paper
raised the possibility of using the system for genome editing in
cells and organisms and that confirmed that it "could
recognize and cleave the target DNA sequence in cultured human
cells." Broad relied on a letter that Dr. Kim sent to the UC
inventors noting that his group had been developing its
genome-editing technology for a "few months" after
reading UC's paper. And UC relied on a number of earlier
successful uses of prokaryotic DNA-targeting proteins in eukaryotic
cells. Such evidence, UC argued, established the requisite
expectation of success in eukaryotic cells. Moreover, UC relied on
the disclosure in Jinek 2012 before Broad filed its first
provisional application of "the potential to exploit the
system for RNA-programmable genome editing" and "the
exciting possibility of developing a simple and versatile
RNA-directed system to generate dsDNA breaks for genome targeting
and editing." As to admissions by UC's inventors tending
to show unobviousness, UC argued that they were irrelevant because
obviousness must be determined from the viewpoint of one of
ordinary skill in the art, not an inventor, and the inventors made
other positive, forward-looking statements before Broad filed its
first provisional application.

In reply, Broad argued that Jinek 2012's spurring others to
adapt CRISPR to eukaryotes, because of the huge award if success
were achieved, evidenced only motivation and a mere possibility of
success, not a reasonable expectation of success. Broad further
argued that prior successes with four prokaryotic proteins in
eukaryotic cells did not provide a reasonable expectation of
success, because "there are thousands of different types of
prokaryotic proteins," and differences between those four
proteins and Cas9 would have discouraged adaptation of the claimed
system to eukaryotic cells. And Broad emphasized that none of those
instances involved an RNA component and that UC's experts
admitted that that was a "major difference." Finally,
Broad relied on a history of failed attempts to adapt prokaryotic
protein-RNA complexes to eukaryotes. As an example, Broad argued
that after 16 years of attempts, researchers had succeeded in
showing Group II introns to function in eukaryotic cells only by
microinjection into an embryonic cell that had its magnesium level
artificially increased. According to Broad, the literature in 2012
uniformly characterized that and other prokaryotic systems
including RNA, citing as examples CRISPR systems, as failures. As
to the later successes by others, Broad argued that they do not
demonstrate the existence of an expectation of success
before the successful experiments, and they were achieved
by extraordinarily skilled persons, not those of ordinary skill in
the art.

Both parties argued similarly well and made similar arguments
regarding UC's motion to substitute Count 1 with proposed Count
2. Indeed, UC's motion is in part the mirror image of
Broad's motion.

That part stems from UC's argument that the limitation of
Count 1 to eukaryotes, which none of UC's designated claims
recites, is not separately patentable (i.e. would have been obvious
in view of UC's claims). Count 1, UC argued, unfairly would
prevent UC from relying on proofs within the scope of its
designated claims because of the limitation to eukaryotes. In
connection with that limitation, omitted from proposed Count 2,
UC's arguments are virtually identical to its arguments in
opposition to Broad's motion for no interference-in-fact, with
one notable exception. UC noted that if, contrary to UC's
position, practicing the invention in eukaryotes is
separately patentable, while none of UC's claims recites that
limitation and all of Broad's claims do, there is no
interference-in-fact and the PTAB should not have declared an
interference. On the other hand, if practicing the invention in
eukaryotes is not separately patentable, as implied by the
declaration of the interference, then the count should not be
limited to that environment.

UC's proposed Count 2, however, includes an additional
limitation that UC contended is separately patentable,
namely replacing the limitation of Count 1 generically permitting
the DNA-targeting RNA to comprise one or more molecules with a
requirement for a single-molecule DNA-targeting RNA, to which UC
further contends all involved claims of both parties are directed.
UC argued that proposed Count 2 is fair to Broad because it does
not exclude its eukaryotic proofs, and Count 2 appropriately
requires a single-molecule DNA-targeting RNA because both
parties' claims are so limited and it is separately
patentable.

Thus, proposed Count 2 reads as follows:

A method of cleaving or editing a target DNA molecule or
modulating transcription of at least one gene encoded thereon, the
method comprising:

an activator-RNA, or a
trans-activating CRISPR RNA (tracrRNA), that hybridizes with the
targeter-RNA to form a double-stranded RNA duplex of a protein
binding segment, and

a Cas9 protein,

wherein i) and ii) are covalently linked to one another, and

wherein a) forms a complex with b), thereby targeting the Cas9
protein to the target DNA molecule, whereby said target DNA
molecule is cleaved or edited or transcription of at least one gene
encoded by the target DNA molecule is modulated.

Proposed Count 2 substantively differs from Count 1 by omitting
the restriction to eukaryotic cells and by limiting the
DNA-targeting RNA to a single molecule as a result of covalent
linking of the targeter-RNA and activator-RNA or tracrRNA. The
proposed count also alternatively identifies the DNA-targeting RNA
as a "guide RNA" because that is the terminology used in
Broad's claims that UC interprets to mean an RNA comprising
both the guide sequence and the tracr sequence.

Since, as noted above, the UC's arguments regarding whether
the count should be limited to eukaryotes are virtually identical
to its arguments regarding Broad's motion for no
interference-in-fact, only UC's arguments regarding the
single-molecule limitation require further discussion.[4] UC argued
that the single-molecule DNA-targeting RNA for Cas9 is separately
patentable because it has received praise and been widely adopted,
while before the publication of Jinek 2012, one of ordinary skill
in the art would not have believed that the DNA-targeting RNA could
be a single molecule and still function with Cas9 to cleave DNA. UC
introduced evidence of the praise and widespread adoption and
evidence that such structural changes were known to cause problems
with enzymatic functions in analogous systems. UC explained that it
interpreted all of Broad's involved claims as reciting a
single-molecule DNA-targeting RNA because "Junior Party's
involved specifications state that the term 'guide RNA' can
be used interchangeably to refer to the single-molecule
DNA-targeting RNA." But UC further argued that any of
Broad's claims that were not so construed would still
correspond to the proposed count because the single-molecule
DNA-targeting RNA of the proposed count would anticipate a generic
guide RNA.

Broad vigorously disagreed that all of its involved claims
recite a single-molecule DNA-targeting RNA, arguing that
"guide RNA" has long been used in the art to encompass
one or more molecules for guiding the RNA to the target and that
the paragraph in UC's application is ambiguous and not a
"clear disavowal" of the ordinary meaning. Broad
therefore asserted that more than 330 of its involved claims
include subject matter outside the scope of proposed Count 2
(although that leaves 55 claims within the scope of the proposed
count) and that the proposed count "therefore fails to
properly define the interfering subject matter."

Broad argued also that proposed Count 2 is unfair because it
excludes Broad's earliest proofs, which use a two-molecule
guide RNA. On the other hand, Broad argued that Count 1 is not
unfair to UC even though it excludes UC's earliest proofs,
because UC sought an interference with Broad's patent claims,
all approximately 400 of which are limited to eukaryotic cells and
were allowed based on the separate patentability of that
limitation, and because UC canceled its claims reciting the
eukaryotic environment to argue that none of its claims recites
that limitation. "It is therefore fair," Broad argued,
"that UC cannot rely on in vitro [prokaryotic] work
to prove priority on this key invention." Of course, Broad,
like UC, repeated its arguments about the patentability of the
eukaryotic environment made in its motion for no
interference-in-fact.

Broad also argued that proposed Count 2 should not be
substituted for Count 1 because the proposed count is not
patentable over the prior art. But Broad's argument appears to
be that if the standard for patentability that UC argued in
opposition to Broad's motion for no interference-in-fact, with
which Broad disagrees, is correct, then proposed Count 2 as well as
the eukaryotic environment would have been obvious in view of the
prior art. But suppose the PTAB concludes that both counts present
separately patentable inventions? Broad did not appear to address
that possibility, which might lead to blocking patents, the
invention of proposed Count 2 to UC and the invention of Count 1 to
Broad.

In its reply, UC again repeated its arguments that the subject
matter of Count 1 would have been obvious and that the count
therefore is improperly limited to eukaryotes. But UC did not
appear to repeat its unfairness argument or deny that it canceled
its claims reciting the eukaryotic environment. UC did repeat its
argument, however, that the subject matter of proposed Count 2 is
separately patentable and claimed by both parties.

Although the parties filed other motions, such as motions for
benefit of provisional applications, decisions on the two motions
addressed in some detail above will probably determine whether the
interference proceeds to a priority phase. If the use of the system
in the eukaryotic environment is ultimately determined to have been
obvious and not separately patentable, Broad might be left
empty-handed and UC might have the exclusive right to this
immensely important technology. But if the use of the system in the
eukaryotic environment is separately patentable, Broad would likely
be the big winner, possibly sharing the spoils with UC, depending
on the outcome with respect to single-molecule DNA-targeting RNA.
Stay tuned.

For physicians considering patents, there are some initial issues to address and then a comprehensive patent strategy to develop before going down the path toward filing an application. Once your patent strategy is in place, you can turn your attention to your patent application

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